New perspectives of curcumin in cancer prevention Wungki ......2 Abstract: Numerous natural compounds have been extensively investigated for their potential for cancer prevention over
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New perspectives of curcumin in cancer prevention
Wungki Park, A.R.M Ruhul Amin, Zhuo Georgia Chen, and Dong M. Shin
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory
University, Atlanta, Georgia, 30322, U.S.A.
Running Title: Curcumin in Cancer Prevention
Key Words: Chemoprevention, Curcumin, Natural compound, Molecular target,
Bioavailability
Financial Support: This work was supported, in whole or in part, by National Institutes of
Health Grants P50 CA128613 (DMS) and R03 CA159369 (ARA) and Robbins Scholar
Award (ARA)
Conflict of Interest: None
Address for Correspondence: Dong M. Shin, Department of Hematology and Medical
Oncology, Winship Cancer Institute of Emory University, School of Medicine, Atlanta,
GA, 30322, U.S.A. Phone: 1-404-778-2980; Fax: 1-404-778-5520; E-mail:
dmshin@emory.edu
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Abstract:
Numerous natural compounds have been extensively investigated for their potential for
cancer prevention over decades. Curcumin, from Curcuma longa, is a highly promising
natural compound that can be potentially used for chemoprevention of multiple cancers.
Curcumin modulates multiple molecular pathways involved in the lengthy carcinogenesis
process to exert its chemopreventive effects through several mechanisms: promoting
apoptosis, inhibiting survival signals, scavenging reactive oxidative species (ROS), and
reducing the inflammatory cancer microenvironment. Curcumin fulfills the
characteristics for an ideal chemopreventive agent with its low toxicity, affordability, and
easy accessibility. Nevertheless, the clinical application of curcumin is currently
compromised by its poor bioavailability. Here we review the potential of curcumin in
cancer prevention, its molecular targets, and action mechanisms. Finally, we suggest
specific recommendations to improve its efficacy and bioavailability for clinical
applications.
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Introduction
Cancer is a major health problem that can debilitate and destroy human lives. One out of
every four deaths in the U.S. is caused by cancer. Over $124.6 billion was spent in direct
medical costs for the 13.7 million cancer survivors and 1.5 million newly diagnosed
cancer patients in the U.S. in 2010. Increasing human life expectancy will inevitably raise
cancer prevalence and the related costs. Consequently, the development of effective
cancer prevention strategies is increasingly important. Histologically, the development of
cancer involves multiple steps, which occur over several years after the initial carcinogen
exposure from normal to hyperplasia, mild, moderate, and severe dysplasia, and
carcinoma in situ, before finally progressing to invasive cancer (1). Throughout this long,
multi-step developmental course, there is a wide scope of possible preventive approaches
that can delay or prevent the development of cancer. Different cancer prevention
strategies such as behavioral modification, vaccines, surgical manipulation, and
chemoprevention have evolved with tremendous research efforts (2). Many investigations
have proven that healthy lifestyles involving balanced diets, regular exercise, smoking
cessation, alcohol reduction, weight control, and stress management are beneficial for
decreasing cancer risk and can never be overemphasized (3-7). One particular milestone
in cancer prevention was the approval by the U.S. Food and Drug Administration (FDA)
of the human papilloma virus (HPV) cervical cancer vaccine in 2009 as a result of
positive randomized controlled clinical trials.
The term chemoprevention was first coined by M. B. Sporn in 1976 who defined it as a
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preventive modality in which natural or synthetic agents can be employed to slow, stop,
reverse, or prevent the development of cancer. Since then, researchers have investigated
numerous agents for the purpose with few successes. The first important translational
study of a potentially chemopreventive agent was conducted with 13-cis retinoic acid
(13-cRA), which resulted in successful size reduction of the premalignant lesion oral
leukoplakia, albeit with some notable toxicities (8). In an attempt to reduce the toxicity,
this study was followed by another trial using high dose isotretinoin induction and
maintenance with isotretinoin or beta carotene, which suggested that isotretinoin is
significantly more effective than beta carotene against leukoplakia (9). Another follow up
study using low dose isotretinoin and a large cohort of patients resulted in a negative
outcome (10). In contrast, the field of breast cancer chemoprevention research gained
considerable momentum after positive large-scale clinical trials of Tamoxifen, a selective
estrogen receptor modulator (SERM), led to its FDA approval (11). However, not all
cancer types have successful chemoprevention stories. In colorectal cancer, despite
positive secondary clinical trials of sulindac, celecoxib, and aspirin, primary prevention
using cyclooxygenase-2 (COX-2) inhibitors was shown to have no benefit in the general
population and the study was terminated early due to cardiovascular toxicity (12-14).
Another disappointment was the recently conducted selenium and vitamin E cancer
prevention trial (SELECT), which gave negative results in patients with lung and prostate
cancers (15). After several large negative clinical trials were reported, the focus of the
new era in chemoprevention has shifted toward molecularly targeted agents and less toxic
natural compounds.
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In chemoprevention, safety of the participants is the first priority and should be
considered of the utmost importance since essentially healthy people will receive the
chemopreventive treatment for a long period of time. Moreover, the toxicity of the agents
could impact patient accrual in larger scale studies in real clinical practice. To this end,
unlike synthetic compounds, the safety of natural compounds present in fruits, vegetables,
and spices are well established through their long-term consumption in human history
(16). Therefore, taking natural compounds for cancer prevention can be a well justified
and effective strategy for people with increased risk for cancer development – such as
those with premalignant lesions of intraepithelial neoplasia. Among many such natural
compounds, curcumin has drawn special attention for its chemoprevention potential
because of its safety, multi-targeted anticancer effects, and easy accessibility (16). The
following sections will discuss different aspects of curcumin as a chemopreventive agent,
including its safety, efficacy, and mechanism of action.
Curcumin in Chemoprevention
Since 1987, the National Cancer Institute (NCI) has tested over 1,000 different potential
agents for chemoprevention activity, of which only about 40 promising agents were
moved to clinical trials (17). Curcumin, present in the Indian spice “haldi”, is one such
agent that is currently under clinical investigation for cancer chemoprevention. Three
polyphenols (Figure 1) were isolated from Curcuma longa, of which curcumin (bis-α,β-
unsaturated β-diketone) is the most abundant, potent and extensively investigated (16).
Curcumin has been used empirically as a remedy for many illnesses in different cultures.
It is only in the last few decades that curcumin’s effects against cancer and cancer
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therapy-related complications have emerged, through much investigation. The first
clinical report of the anticancer properties of curcumin was from Kuttan and coworkers,
who used 1% curcumin ointment on skin cancerous lesions with a reduction in smell in
90% of patients (18). 10% patients experienced a reduction in pain and lesion size. In an
experimental model of mammary cancer induced by 7,12-dimethylbenz-[a]-anthracene
(DMBA) in female rats, the initiation of DMBA-induced mammary adenocarcinoma was
significantly decreased by intraperitoneal infusion of curcumin 4 days before DMBA
administration (19). In a study of esophageal cancer prevention in curcumin-fed F344 rats,
the chemopreventive activity of curcumin was observed not only in the initiation phase
but also in post-initiation phases (20). Also, in a familial adenomatous polyposis (FAP)-
simulated study in which the APC gene of C57Bl/6J Min/+ mice was mutated to result in
the development of numerous adenomas by 15 weeks of age, an oral curcumin diet
prevented adenoma development in the intestinal tract, suggesting the chemopreventive
effect of curcumin in colorectal cancer with APC mutation (21). Moreover, in a rat model
of N-nitrosodiethylamine and phenobarbital-induced hepatic cancer, curcumin reduced
lipid peroxidation and salvaged hepatic glutathione antioxidant defense, which eventually
may have contributed to hepatic cancer prevention (22). Several studies of cancer
prevention at different stages have demonstrated the multi-targeted anticancer and
chemopreventive effects of curcumin and have suggested it as a very favorable agent for
chemoprevention.
Mechanisms of Anticancer Effects
According to their mode of action, chemopreventive agents are classified into different
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subgroups: antiproliferatives, antioxidants, or carcinogen blocking agents. Curcumin
belongs to all three subgroups, given its multiple mechanisms of action. The anticancer
effects of curcumin mainly result from multiple biochemical mechanisms that are
involved in the regulation of programmed cell death and survival signals. The curcumin
targets that are involved in signaling pathways include transcription factors, growth
factors, inflammatory cytokines, receptors, and enzymes (Figure 2). In different types of
cancers, curcumin exhibits anticancer actions through a combination of different
mechanisms including; survival signal reduction, proapoptotic promotion, anti-
inflammatory actions, and reactive oxygen stress (ROS) scavenging to different degrees.
The effects of curcumin on these signaling pathways are expected to be more complicated
in the real setting, and the mechanisms of curcumin’s chemopreventive, chemosensitizing,
and radiosensitizing effects are more vigorously being studied now.
Survival signals - nuclear factor-κB (NF–κB)
The survival signals in cancer cells are upregulated to support proliferation and survival
against anticancer treatment. The central role players in this process are nuclear factor-κB
(NF-κB), Akt, and their downstream cascades that can lead to the upregulation of anti-
apoptotic Bcl-2 proteins. Curcumin can modulate these signals by inhibiting the NF-κB
pathways at multiple levels (23, 24). Curcumin significantly inhibited the growth of
squamous cell carcinoma of head and neck (SCCHN) xenograft tumors in nude mice.
Inhibition of nuclear and cytoplasmic IκB-β kinase (IKKβ) in the xenograft tumors
decreased NF-κB activity (25). Curcumin was also shown to enhance chemosensitivity in
5-fluorouracil and cisplatin treated esophageal adenocarcinoma as well as in paclitaxel
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treated breast cancer cells by inhibiting compensatorily upregulated NF-κB (26).
Likewise in a colon cancer cell line during radiotherapy, curcumin blocked NF-κB and
reduced radioresistance (27).
Apoptotic signals – intrinsic and extrinsic
Curcumin induces programmed cell death (apoptosis) in many cancer cell types. Both the
intrinsic and extrinsic apoptotic pathways are activated by curcumin. In the intrinsic
pathway, various cell stresses – irreversible DNA damage, defective cell cycle, or loss of
growth factors – can generate death signals and ultimately pass them down to
mitochondria. Then, depending on the balance of Bcl-2 family members, the destiny of
the cell is driven into apoptosis. Curcumin upregulates the p53 modulator of apoptosis
(PUMA) and Noxa, which, in turn, activates the proapoptotic multi-domain Bcl-2 family
members Bax, Bim, and Bak and downregulates Bcl-2 and Bcl-xl. Loss of balance
between pro- and anti-apoptotic Bcl-2 proteins causes calcium influx into mitochondria
and decrease in mitochondrial outer membrane permeability (MOMP) which allows
cytochrome C and Smac release into the cytoplasm, eventually leading to the activation
of a cascade of caspases and formation of the apoptosome, causing apoptosis (28).
In the extrinsic pathway, death signals are initiated from the exterior environment of the
cells via Fas, tumor necrosis factor (TNF), and death receptors (DR) 3-6. When the signal
is received, conformational change in the receptors allows Fas-associated death domain
(FADD) binding and recruits the death-induced signaling complex (DISC), which
activates the formation of initiator caspases 8 and 10. Curcumin was shown to upregulate
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extrinsic apoptosis pathway signals via the Fas pathway. In TNF-related apoptosis
inducing ligand (TRAIL)-resistant cell lines, curcumin also enhanced apoptosis by
upregulating the expression of DR 4 and 5 (29). After DISC recruitment, activation of the
initiator caspases is regulated by FLICE-like inhibitory protein (FLIP) and curcumin was
shown to downregulate c-FLIP in natural killer/T-cell lymphoma (30). Afterwards, the
initiator caspase cleaves Bid and the truncated Bid (tBid) provides crosstalk between the
intrinsic and extrinsic pathways by delivering death signals from initiator caspases
directly to the mitochondrial pathway. In SKOV3 and OVCA429 ovarian carcinoma cells,
curcumin showed induction of both intrinsic and extrinsic apoptosis by cleavage of pro-
caspase 3, 8, 9 and cytochrome C release followed by tBid formation (31).
p53 plays a major role in tumor development and treatment, however, more than 50% of
all cancers have p53 mutations. p53 proofreads DNA and recognizes uncorrectable
mutations, at which point it arrests the cell cycle and steers the cell toward programmed
cell death. Curcumin was shown to upregulate p53 expression followed by an increase in
p21 (WAF-1/CIP-1), resulting in cell cycle arrest at G0/G1 and/or G2/M phases. This is
eventually followed by the upregulation of Bax expression, which induces apoptosis (32).
On the other hand, curcumin has also showed its p53-independent anticancer effect as an
inhibitor of the proteasome pathway by inhibiting ubiquitin isopeptidase (33). In a
prostate cancer cell line, curcumin downregulated MDM2, the ubiquitous ligase of p53,
and displayed enhanced anticancer effect via PI3K/mTOR/ETS2 pathways in PC3
xenografts in nude mice receiving gemcitabine and radiation therapy (34). In p53 mutant
or knockout ovarian cancer cell lines, curcumin induced p53-independent apoptosis
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which involved p38 mitogen-activated protein kinase (MAPK) activation and inhibited
Akt, resulting in decreased expression of Bcl-2 and survivin (31). Taken together, cancers
with both deleted/mutant and wild-type p53 can benefit from curcumin treatment to
achieve an anticancer effect.
Trophic signals – growth factors and cytokines
Different kinds of trophic factors including growth factors and cytokines can contribute
to growth signals in cancer cells. Curcumin inhibits epidermal growth factor receptor
(EGFR) kinase phosphorylation and strongly degrades Her2/neu protein, which
ultimately inhibits cancer growth (35). In SCCHN, curcumin targets both EGFR and
vascular endothelial growth factor (VEGF) to inhibit cell growth (36). Therefore, the
multi-targeted activity of curcumin may be potentially more effective. In an estrogen
receptor negative breast cancer cell line, curcumin inhibited angiogenesis factors such as
VEGF and basic fibroblast growth factor (b-FGF) at the transcriptional level (37).
Curcumin was also shown to inhibit expression of pro-inflammatory cytokines such as
IL-1β and -6 and exhibited growth inhibitory effects through inhibition of the NF-κB and
MAPK pathways (38). In a breast cancer cell line, curcumin was shown to inhibit
phosphorylation of Akt within the MAPK/PI3K pathway, which led to proapoptosis (39).
Roles of reactive oxidative stress (ROS)
ROS has opposing effects on cancers: it can be an insult causing DNA mutations in
carcinogenesis, and it can also drive mitochondrial apoptosis. Minimizing DNA insult by
scavenging ROS is important for the prevention of cancer, whereas generating ROS to
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drive mitochondrial apoptosis is more important when treating malignancies. In terms of
ROS scavenging, curcumin was shown to induce phase II metabolizing enzymes in male
mice – glutathione-S-transferase (GST) and quinine reductase, which can neutralize ROS
derived from chemical carcinogens (40). Also, curcumin was shown to induce another
important ROS scavenging enzyme – hemeoxygenase-1, the redox-sensitive inducible
enzyme, via nuclear factor 2-related factor (Nrf-2) regulation (41). Curcumin is a ROS
scavenging enzyme inducer but on the other hand, it also uses ROS to kill cancer cells.
ROS generated by curcumin in human renal Caki cells downregulated Bcl-xl and
inhibitors of apoptosis proteins (IAP), thereby inducing apoptosis (42). In cervical cancer
cell lines, curcumin-generated ROS activated extracellular signal-regulated kinase (ERK)
which modified radiosensitivity (43). Despite the paradoxical roles of curcumin in
scavenging and generating ROS, the overall effect of curcumin is an anticancer activity.
Microenvironments – inflammation
Regarding the cancer microenvironment, the anticancer effect of curcumin is also
described as an antagonist to leaky vessels and loss of adhesion, which are closely related
to cancer development and invasiveness. The relationship between the proinflammatory
enzymes COX-2 and lipoxygenase (LOX) and the possible development of colorectal,
lung, and breast cancers has been investigated (44). In colorectal cancer, development of
the premalignant lesion aberrant crypt foci (ACF) was shown to be related to upregulated
COX-2 level via inducible nitric oxide synthase (iNOS). As a non-specific iNOS
inhibitor, curcumin significantly inhibited colonic ACF formation in F344 rats (45).
Curcumin also downregulates CXCL-1 and -2 via NF-κB inhibition and, accordingly,
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downregulates the metastasis-promoting gene CXCR4 in a breast cancer cell line (46). In
the normal Wnt pathway, β-catenin participates in the regulation of cell-to-cell adhesion
integrity but in certain cancers, aberrant β-catenin accumulation promotes survival
through an upregulated Akt pathway. In colon cancer cells, curcumin promoted caspase-
3-mediated cleavage of β-catenin and decreased the level of the oncogene c-Myc (47).
Additionally, the invasiveness/metastasis of cancers was shown to be related to matrix
metalloproteinase-9 (MMP-9) secretion, and treatment of an invasive hepatocellular
cancer cell line with curcumin resulted in diminished invasiveness due to inhibition of
MMP-9 secretion by curcumin (48).
Cancer stem cells (CSCs) and miRNA
Cancer stem cells (CSCs) are a rare population of cells within the tumor having cell
renewal properties and are thought to be responsible for tumor initiation and treatment
failures. The cancer stem-cell concept has important implications for cancer therapy and
targeting CSCs is a relatively new strategy that can decrease cancer recurrence and
relapse and treatment failure. Several studies have suggested that curcumin and its
analogs can also target CSCs. In prostate cancer cells under hypoxic conditions, the
curcumin analog CDF decreased CSC markers such as Nanog, Oct4, and EZH2 as well as
miR-21, which contributed to deregulation of CSC function through the effects of CDF
on the hypoxic pathway via HIF-1α (49). In colon cancer cells, STAT3 overexpression
was found in ALDH(+)/CD133+ CSCs. The curcumin analog GO-Y030 inhibited the
expression of STAT3 expression and suppressed CSC growth in colon cancer cells (50).
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Also in the rat glioma cell line C6, curcumin was shown to decrease the side population
which is known to be associated with stem cell populations (51).
MicroRNAs (miR) also play essential roles in tumorigenesis and anticancer drug
development because of their ability to target both tumor suppressor and oncogenes.
Curcumin and its analogs also target miR, which contributes to their chemopreventive
potential. By controlling epigenetic gene expression via EZH2-miR regulation, CDF
increased the levels of tumor-suppressive miR that are mostly absent in pancreatic cancer
cells including let-7a, b, c, d, miR-26a, miR-101, miR-146a, and miR-200b, c and
resulted in decreased pancreatic cancer cell survival and aggressiveness (49). Curcumin
and its cyclohexanone and piperidine analogs inhibited growth of multiple colon cancer
cells by targeting Sp transcription factors (52). Induction of the Sp repressors ZBTB10
and ZBTB4 and downregulation of miR-27a, miR-20a and miR-17-5p by these
compounds are important for inhibiting Sp transcription factors. miR-203 is also a target
of curcumin in bladder cancers that regulates the Src-Akt axis (53).
Curcumin and host factors: Immunomodulation and metabolism
Due to poor bioavailability, it is practically impossible to reach the in vitro effective dose
of curcumin in vivo. Still, curcumin is effective in vivo in inhibiting tumor growth and
modulating biomarkers, suggesting that the host factors such as the host immune system
and metabolic systems have an effect on its activities. Lack of functional T-cells or T-cell
derived cytokines like interferon-γ promotes spontaneous as well as carcinogen-induced
tumorigenesis. CD8(+) cytotoxic T lymphocytes (CTLs) are involved in antigen-specific
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tumor destruction and CD4(+) T cells are essential for helping this CD8(+) T cell-
dependent tumor eradication. Curcumin prevented loss of T cells, expanded T cell
populations and reversed the type 2 immune bias and attenuated the tumor-induced
inhibition of T-cell proliferation in tumor-bearing hosts (54). Moreover, curcumin
inhibited the production of immunosuppressive cytokines such as TGF-B and IL-10 in
these hosts. Another study suggested that increased CD8+ T cells enhance the production
of INF-γ by curcumin (55). Another host effect is on the metabolism of curcumin, which
involves two routes: one route transforms curcumin to hexahydrocurmin through
successive reductions (probably through the intermediates dihydrocurcumin and
tetrahydrocurcumin), the other route involves rapid molecular modification by
conjugation to glucuronide, sulfate and glucuronide–sulfate forms (56). Although the
main curcumin metabolites remain controversial, both in vivo and in vitro cell free studies
suggest that hydrocurcumins are more potent antioxidants than parent curcumin in
scavenging free radicals, reducing lipid peroxidation and in enzyme activation (of
superoxide dismutase, catalase, GSH peroxidase and GST) (57, 58). These antioxidant
effects were shown to be critical for the chemopreventive potential of curcumin. Thus,
curcumin displayed efficacy in vivo probably due to the presence of these host effects.
Clinical Trials of Curcumin Use in Cancer
Many positive preclinical cell line and animal model studies have brought curcumin to
clinical trials to test its safety and efficacy as a chemopreventive agent. Several clinical
trials have already been completed, the results of which are summarized in Table 1 (59-
68). In phase I trials, curcumin was tested for its toxicity and tolerability, and was found
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to be highly tolerable at doses up to 12 g/day with no curcumin-related toxicities (60, 61).
However, due to its poor bioavailability, curcumin was not detectable in blood when
administered at doses up to 8 g, and was detected at very low levels following 10 g and
12 g doses with a peak concentration at 1~2 hours. Histological improvements of the
lesions were observed in most of the treated patients (60). Radiologically stable disease
was also demonstrated in five out of fifteen colorectal cancer patients who were
refractory to chemotherapy in a second study (61). In a colorectal cancer trial, curcumin
was shown to modulate biomarkers such as GST activity, deoxyguanosine adduct M(1)G,
and PGE2 (prostaglandin E2) (61-63). A decrease in lymphocytic GST activity of 59%
resulted after administration of 440 mg of Curcuma extract (61). The levels of M(1)
decreased from 4.8 +/- 2.9 adducts per 107 nucleotides to 2.0 +/- 1.8 adducts per 107
nucleotides after curcumin administration (63). Oral administration of 3.6 g curcumin
significantly ((P < 0.05) decreased inducible PEG2 production in blood 1 hour after
curcumin administration as compared to the predose level (62). The same study also
demonstrated the poor bioavailability and systemic distribution of curcumin. After
encapsulated curcumin was administered in different amounts ranging from 0.45 to 3.6 g
for 4 months, its biodistribution was examined by biopsy which showed malignant
mucosal tissue had a higher concentration of curcumin whereas outside the mucosa, only
a negligible amount was found (61). This result may also be very beneficial for colorectal
malignancy because any possible toxicity outside of the area of interest can be minimized.
In one study where five FAP patients who had prior colectomy were treated with the
combination of curcumin and quercetin for 6 months, the size and number of adenomas
were reduced significantly, supporting the use of curcumin for FAP colorectal cancer
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prevention (66). Administration of 4 g curcumin per day for 30 days significantly
inhibited (40%) the number of ACF although the 2 g per day dose was found to be
ineffective (68). Several patients with advanced pancreatic cancers also responded to 8
g/day of curcumin treatment (69). These promising results are very convincing but need
to be validated with further larger-scale randomized trials. Table 2 shows ongoing clinical
studies with curcumin.
Biomarkers in Curcumin Chemoprevention Trials
Biomarkers can be very useful in identifying high risk subjects for intervention,
monitoring the effects of treatment, predicting outcome and selecting patients who may
benefit most from a given intervention. A well validated biomarker may also serve as a
surrogate endpoint to replace the current use of size reduction or histologic improvement
of the precancerous lesion as the sole measure of success of chemoprevention; the use of
a surrogate marker would potentially provide a more accurate assessment of outcome and
would resolve the current difficulty in patient accrual due to the requirement for biopsy in
chemoprevention clinical trials.
Although biomarkers for chemoprevention by curcumin have been extensively studied in
cell culture and rodent models, only a few clinical studies have focused on biomarker
modulation and attempted to correlate these with outcomes. In a recent pilot study, IKKβ
kinase activity and the levels of proinflammatory cytokine IL-8 in the saliva of SCCHN
patients were measured and the results suggested that IKKβ kinase activity could be used
to detect the effect of curcumin treatment in SCCHN (70). In a double blind randomized
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trial, curcumin was found to significantly decrease the levels of serum calcitonin gene-
related peptide (CGRP) as compared to placebo (71). There were also significant
decreases in serum IL-8 and high-sensitivity C-reactive protein (hs-CRP) in both
curcumin and placebo group with a higher magnitude in the curcumin group. In a
placebo-controlled study, oral administration of curcumin significantly reduced
erythrocyte malonaldehyde (MDA) and increased GSH levels in patients with tropical
pancreatitis (72). Curcumin was also found to significantly decrease the serum levels of
markers of oxidative damage (MDA, 8-hydroxydeoxyguanosine) and increase those of
antioxidants (vitamins C and E) in patients with oral leukoplakia, oral submucous fibrosis
or lichen planus along with a significant decrease in pain and lesion size (73). Another
clinical study suggested that cytokines and NF-kB pathway markers are important targets
for curcumin chemoprevention (69). Other enzymes including COX-2 and hepatic GST
nucleotidase have also been suggested for use in monitoring the effect of curcumin in
chemoprevention studies (74). Also, in a recent phase IIa clinical trial of curcumin
chemoprevention in colorectal neoplasia, although the levels of PGE2 and 5-HETE did
not significantly correlate with curcumin treatment, the amount of the premalignant
lesion ACF was decreased (68), while other studies showed marked modulation of PGE2
(62). To clarify these ambiguous results, many more clinical studies testing different
surrogate biomarkers in larger patient numbers must be performed to overcome the
limitations to the study of surrogate monitoring biomarkers. Based on these previous
results, however, biomarkers of oxidative stress, NF-kB pathway markers and cytokine
levels in serum and tissues appear to be promising markers that new studies should be
designed to measure.
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Hurdles: Pharmacokinetics and Pharmacodynamics
Phase I/II clinical trials have clearly shown that curcumin exhibits poor bioavailability in
humans, ~1% after oral administration, a major barrier for its use in the clinic. The major
factors contributing to the low plasma and tissue levels of curcumin appear to be its poor
absorption due to insolubility in water, rapid systemic elimination in the bile and urine
due to extensive enterohepatic recirculation and fast metabolism (56). In fact, 40% of
orally administered curcumin is excreted unchanged in the feces. To circumvent the
bioavailability problem, numerous approaches have been considered, including structural
modification or modification of the delivery system such as adding adjuvant, liposomal
curcumin, curcumin nanoparticles and phospholipid complex.
Curcumin analogs: Studies suggest that the β-diketone moiety is responsible for the
instability and weak pharmacokinetic profile of curcumin. Modifications of the structure
of natural curcumin significantly improved solubility, stability and bioavailability. James
Snyder’s group at Emory University has synthesized a series of curcumin analogs by
modifying the diketone moiety and the side chains of the benzene rings. Many of these
compounds showed increased water solubility and improved pharmacokinetic properties
including tissue distribution and terminal elimination half life (75). Analog HO3867 also
showed tremendous improvement in cellular uptake and tissue distribution as compared
to its natural counterpart (76). Gagliardi et al., (77) synthesized more than 40 curcumin
analogs and studied the bioavailability of some of these compounds in mice. One
particular compound with a valine substitution at the phenyl ring showed more than 50-
fold greater bioavailability than natural curcumin. A Japanese group also synthesized 86
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different analogs of curcumin and determined their IC50 against 16 cancer cell lines.
Many of these analogs, namely GO-Y078, 079, 030, 097, and 098, were at least 10-fold
more potent than natural curcumin. This set of compounds is also more soluble in water
suggesting that they might show better bioavailability also (78). Another synthetic
curcumin known as dimethoxycurcumin exhibited significantly higher stability in vivo
and against microsomal metabolism (79). In attempts to overcome the poor
bioavailability of curcumin and to increase its tumor-specificity, many more innovative
analogs have also been studied (Table 3) (80-93).
Curcumin nanoparticles: Delivery of drugs via their formulation as nanoparticles is an
emerging platform for an efficient approach to improve pharmacokinetic properties such
as solubility and stability, and thus bioavailability of poorly bioavailable drugs. This
approach has been extensively used for curcumin with success in preclinical studies.
Formulation of curcumin by encapsulation in polymeric micelles, liposomes, polymeric
nanoparticles, lipid-based nanoparticles and hydrogels makes the formulation aqueous
soluble (56). Many of these formulations also showed improved bioavailability and
pharmacokinetic properties in vivo. Encapsulation of curcumin in polylactic-co-glycolic
acid (PLGA) and PLGA-polyethylene glycol (PEG) (PLGA-PEG) blend nanoparticles by
a single-emulsion solvent-evaporation technique increased its mean half-life to
approximately 4 and 6h, respectively, C(max) by 2.9- and 7.4-fold and bioavailability by
15.6- and 55.4-fold, respectively (94). Encapsulation of curcumin in poly(butyl)
cyanoacrylate (PBCA) nanoparticles led to a 52-fold increase in elimination half-life and
2-fold increase in AUC (95). Curcumin encapsulated in MePEO-b-PCL micelles also
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showed similar improvements in pharmacokinetics parameters (96). Formulation of
curcumin in solid-lipid nanoparticles also tremendously increased its bioavailability
(more than 80-fold higher concentration in blood) (97).
Curcumin conjugates: Conjugation of curcumin with polymers or other lipophilic
compounds is another widely used approach to improve the water solubility and stability
of curcumin. Conjugation of curcumin with hyaluronic acid or polyvinylpyrrolidone
forms water soluble micelles with improved stability at physiological pH and cytotoxic
activities (98, 99). Polymerization of curcumin using diacid also produced a water soluble
curcumin polymer with improved anti-cancer activity (100). Complexation of curcumin
with phosphatidylcholine also significantly (3-20‒fold) improved its pharmacokinetic
parameters, including bioavailability in animal models (101).
Adding adjuvant: One of the major reasons for the poor bioavailability of curcumin is its
rapid glucuronidation. Protection of curcumin from such metabolic conversion using an
adjuvant was found to be successful in improving its bioavailability. Piperine is an
inhibitor of intestinal and hepatic glucuronidation. Concomitant administration of
curcumin with piperine increased the bioavailability of curcumin by 1100% in human
volunteers and 154% in rats (59).
Future Possibilities
High risk individuals and cancer survivors alike may benefit from chemoprevention, not
only because primary cancer chemoprevention is beneficial for high risk groups but also
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because of the devastating nature of the disease course when patients experience SPT or
recurrence. As curcumin is a non-prescription dietary derivative that has multiple targets
at different levels in multiple pathways, it has great potential in the prevention of cancer
and SPT. When its systemic bioavailability is increased through the development of
different analogs and formulations, the promise of curcumin in chemoprevention may be
feasible in many cancer types, not necessarily limited only to gastrointestinal cancers. A
number of new analogs and formulations have already been developed with higher
systemic bioavailability and potency. More standardized clinical trials for bioavailability
and randomized control trials for efficacy should validate the potential of these newer
agents and formulations. First, specific trials can improve the application of curcumin
through changing the route of administration, achieve targeted delivery straight to the
lesion sites by increasing tumor-specific affinity, and develop different analogs that can
bypass or minimize the first-pass metabolism occurring in the gastrointestinal mucosa
and liver. Second, to minimize its metabolism before reaching the targeted site, different
preparations of curcumin may improve its delivery to the target and therefore increase its
bioavailability. Third, formulating curcumin using nanoparticles and microparticles,
which are among the most innovative modalities that can maximize delivery to a target
tissue and increase sensitivity and specificity, may enhance its therapeutic index.
Defining the optimal precancerous candidates and surrogate endpoints to properly assess
chemopreventive response is mandatory in chemoprevention research. Although we
expect the network of signaling pathways to be considerably more complicated than we
currently understand, further studies will better dissect the molecular effects of curcumin
in different cancers. Specifically, microarray or recently developed RNASeq studies may
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be particularly valuable in defining unknown positive and negative signaling loops, and
may represent a new field of future research directed at understanding the critical factors
necessary for chemoprevention. In the future, targeting specific patient populations with
certain biomarkers, so-called tailored chemoprevention, is necessary. Defining critical
biomarkers will help to better design a personalized plan for tailored chemoprevention.
Progress in personal genome-based risk assessment and profiling of individual patients
may also help to identify the patient population best suited to curcumin chemoprevention
in the future.
Acknowledgements
We thank Anthea Hammond for editorial assistance. This work was supported, in whole
or in part, by National Institutes of Health Grants P50 CA128613 (DMS) and R03
CA159369 (ARA). ARA is a recipient of Robbins Scholar Award.
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NF-kappaB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. Int Immunopharmacol 2012; 12:368-77. 85. Devasena T, Menon VP, Rajasekharan KN. Prevention of 1,2-dimethylhydrazine-induced circulatory oxidative stress by bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione during colon carcinogenesis. Pharmacol Rep 2006; 58:229-35. 86. Devasena T, Menon Venugopal VP, Rajasekaran KN. Chemoprevention of colon cancer by a synthetic curcumin analog involves amelioration of oxidative stress. Toxicol Mech Methods 2005; 15:355-9. 87. Kanwar SS, Yu Y, Nautiyal J, Patel BB, Padhye S, Sarkar FH, et al. Difluorinated-curcumin (CDF): a novel curcumin analog is a potent inhibitor of colon cancer stem-like cells. Pharm Res 2011; 28:827-38. 88. Padhye S, Banerjee S, Chavan D, Pandye S, Swamy KV, Ali S, et al. Fluorocurcumins as cyclooxygenase-2 inhibitor: molecular docking, pharmacokinetics and tissue distribution in mice. Pharm Res 2009; 26:2438-45. 89. Fossey SL, Bear MD, Lin J, Li C, Schwartz EB, Li PK, et al. The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines. BMC Cancer 2011; 11:112. 90. Bill MA, Fuchs JR, Li C, Yui J, Bakan C, Benson DM Jr, et al. The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity. Mol Cancer 2010; 9:165. 91. Sato A, Kudo C, Yamakoshi H, Uehara Y, Ohori H, Ishioka C, et al. Curcumin analog GO-Y030 is a novel inhibitor of IKKbeta that suppresses NF-kappaB signaling and induces apoptosis. Cancer Sci 2011; 102:1045-51. 92. Shibata H, Yamakoshi H, Sato A, Ohori H, Kakudo Y, Kudo C, et al. Newly synthesized curcumin analog has improved potential to prevent colorectal carcinogenesis in vivo. Cancer Sci 2009; 100:956-60. 93. Aggarwal S, Ndinguri MW, Solipuram R, Wakamatsu N, Hammer RP, Ingram D, et al. [DLys(6)]-luteinizing hormone releasing hormone-curcumin conjugate inhibits pancreatic cancer cell growth in vitro and in vivo. Int J Cancer 2011; 129:1611-23. 94. Khalil NM, do Nascimento TC, Casa DM, Dalmolin LF, de Mattos AC, Hoss I, et al. Pharmacokinetics of curcumin-loaded PLGA and PLGA-PEG blend nanoparticles after oral administration in rats. Colloids Surf B Biointerfaces 2013; 101:353-60. 95. Duan J, Zhang Y, Han S, Chen Y, Li B, Liao M, et al. Synthesis and in vitro/in vivo anti-cancer evaluation of curcumin-loaded chitosan/poly(butyl cyanoacrylate) nanoparticles. Int J Pharm 2010; 400:211-20. 96. Ma Z, Shayeganpour A, Brocks DR, Lavasanifar A, Samuel J. High-performance liquid chromatography analysis of curcumin in rat plasma: application to pharmacokinetics of polymeric micellar formulation of curcumin. Biomed Chromatogr 2007; 21:546-52. 97. Wang W, Zhu R, Xie Q, Li A, Xiao Y, Li K, et al. Enhanced bioavailability and efficiency of curcumin for the treatment of asthma by its formulation in solid lipid nanoparticles. Int J Nanomedicine 2012; 7:3667-77. 98. Manju S, Sreenivasan K. Conjugation of curcumin onto hyaluronic acid enhances its aqueous solubility and stability. J Colloid Interface Sci 2011; 359:318-25.
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Figure Legends:
Figure 1. Chemical structure of three polyphenols from Curcuma longa
Figure 2. Molecular targets of curcumin. C: Curcumin, CIAP: cleavage inhibitor of
apoptosis, FADD: Fas-associated protein with death domain, FLIP: FLICE-like inhibitory
protein, DISC: Death-inducing signaling complex, MOMP: Mitochondrial outer
membrane permeabilization, PKC: Protein kinase C, PLC: phospholipase C, XIAP: X-
linked inhibitor of apoptosis protein, VEGF: vascular endothelial growth factor, FGF:
fibroblast growth factor, PDGF: Platelet-derived growth factor, EGF: epidermal growth
factor.
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Curcumin
Bisdemethoxycurcumin
Demethoxycurcumin
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Table 1: Completed clinical trials using curcumin
Type Method and material Results and Conclusion ReferencePhase I Safety trial
Patients: 10, 2000 mg/day + piperine 20 mg/kg;
Piperine, a known inhibitor of hepatic and intestinal glucuronidation enhanced serum concentration, extent of absorption, and bioavailability. Much higher concentration with piperine at 1/4 to 1 h post drug (P < 0.01 at 0.25 h and 0.5 h; P < 0.001 at 1 h)
Shoba et al. 1998 (58)
Phase I Safety trial
Patients: 25, Oral 500–12,000 mg/d for 90 days Bx done after treatment
Oral curcumin is not toxic to humans up to 8,000 mg/d for 3 months. Histologic improvement of precancerous lesions were observed in bladder cancer, oral leukoplakia, intestinal metaplasia of the stomach, CIN, and Bowen’s disease
Cheng et al. 2001 (59)
Phase I Colon cancer
Patients: 15, Oral curcumin extract of 440–2200 mg/d for 120 days. Activity of GST and levels of M1G were measured.
Safe administration of curcumin extract at doses up to 2.2 g daily, equivalent to 180 mg of curcumin. Curcumin has low oral bioavailability in humans and may undergo intestinal metabolism. Lowered GST (Glutathione-S-transferase) with constant M1G.
Sharma et al.2001 (60)
Phase I Colorectal cancer
Patients: 15, Oral 450–3600 mg/d for 120 days. Dose-escalation study. Levels of curcumin and its metabolites in plasma, urine, and feces were measured.
Lowered inducible serum PGE2 levels (P < 0.05). No dose-limiting toxicity. A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the cancer prevention outside the gastrointestinal tract. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.
Sharma et al.2004 (61)
Phase I Colorectal cancer
Patients: 12, Oral 450–3600 mg/d for 7 days. Bx samples of normal and malignant colorectal tissue, at diagnosis and at 6 to 7 hours after last dose of curcumin.
M1G levels were 2.5-fold higher in malignant tissue as compared with normal tissue (P < 0.05 by ANOVA). The concentrations in normal and malignant colorectal tissue of patients receiving 3,600 mg of curcumin were 12.7±5.7 and 7.7±1.8 nmol/g, respectively. The daily dose of 3.6 g curcumin achieves pharmacological efficacy in the colorectum with negligible distribution of curcumin outside the gut.
Garcea et al.2005 (62)
Phase I Safety trial
Patients: 24, Oral 500–12,000 mg/day. Dose-escalation study for MTD and safety
Seven of 24 subjects (30%) experienced only minimal toxicity. Systemic bioavailability of curcumin or its metabolites may not be essential for CRC chemoprevention because CRC can still benefit from curcumin.
Lao et al.2006 (63)
Phase I Open-label
Patients: 14, Docetaxel (100
MTD at 8,000 mg/d8/14 patients had measurable lesions, with 5 PR
Bayet-Robertet al. 2010
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Advanced metastatic breast cancer
mg/m2) 1 h i.v. every 3 wk on d 1 x six cycles + Oral 500 mg/d for 7 consecutive days and escalated the dose until toxicity. VEGF, and tumor markers measured
and 3 SD. Some biological and clinical responses were observed in most patients. The recommended dose of curcumin is 6,000 mg/d for seven consecutive d every 3 wk in combination with a standard dose of docetaxel.
(64)
Phase II Efficacy trial Skin lesion
Patients: 62, 1% ointment, several months for “External cancerous lesion”
The first clinical study.Reduction in smell in 90% patients, reduction of itching in all cases, dry lesions in 70% patients, reduction in lesion size and pain in 10% patients.
Kuttan et al.1987 (17)
Phase II FAP
Patients: 5, Oral curcumin 480g + quercetin 20 mg tid for 180 days. Polyps size and # assessed
Decrease in the number of polyps was seen in 60.4% Decrease in the size of polyps was 50.9% in FAP patients. RCT in the future are necessary
Cruz-Correaet al. 2006 (65)
Cohort study PIN
Patients: 24 Zyflamend, a novel herbal anti-inflammatory mixture, as a potential chemoprevention agent in a phase I trial for patients diagnosed with PIN.
Rafailov et al.2007 (66)
Phase IIa Patients: 44 40% reduction in ACF numbers with 4g dose
Carroll et al. (67)
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Table 2-Ongoing clinical trials with curcumin
Trial type Official title Cancer type Identifier number
Phase 1 Non-randomized
Phase I Study of Surface-Controlled Water Soluble Curcumin (THERACURMIN CR-011L) in Patients With Advanced Malignancies
Advanced malignancies
Safety/Efficacy Study Single Group Assignment Open Label
NCT 01201694
Phase 1 Non-randomized
Phase I Pharmacokinetic Trial of Curcuminoids Administered in a Capsule Formulation
Colon cancer Pharmacokinetics study Single Group Assignment Open Label
NCT 00027495
Phase 1 Randomized controlled trial Recruiting
Phase I Clinical Trial Investigating the Ability of Plant Exosomes to Deliver Curcumin to Normal and Malignant Colon Tissue
Colon cancer Bioavailability Study Factorial Assignment Open Label
NCT 01294072
Phase 1 Randomized controlled trial
Crossover, Multiple Dose Pharmacokinetics of Two Curcumin Formulations in Healthy Volunteers
Healthy volunteers
Pharmacokinetics Study Crossover Assignment Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
NCT 01330810
Phase 1 Non-randomized
Curcumin Chemoprevention of Colorectal Neoplasia (Curcumin biomarker)
Colorectal cancer
Pharmacodynamics Study Single Group Assignment Intervention Open Label
NCT01333917
Phase 1 Randomized controlled trial
Pilot Study of Curcumin, Vorinostat, and Sorafenib in Patients With Advanced Solid Tumors
Advanced solid tumor
Safety/Efficacy Study Single Group Assignment Open Label
NCT 01608139
Phase 2 Randomized controlled trial
Phase II Double Blind Placebo-Controlled Trial of Curcuminoids' Effect on Cellular Proliferation, Apoptosis and COX-2 Expression in the Colorectal Mucosa of Subjects With Recently Resected Sporadic Adenomatous Polyps
Colorectal cancer
Safety/Efficacy Study Parallel Assignment Double Blind
(Subject, Investigator)
NCT 00118989
Phase 2 Non-randomized
Phase II Trial of Curcumin in Cutaneous T-cell Lymphoma Patients
Cutaneous T-Cell Lymphoma
Efficacy Study Single Group Assignment Open Label.
NCT 00969085
Phase 2 Non-randomized
Phase II Trial of Curcumin in Patients With Advanced Pancreatic Cancer
Advanced pancreatic cancer
Safety/Efficacy Study Single Group Assignment Open Label.
NCT 00094445
Phase 2 Randomized controlled trial Recruiting
Curcumin for Treatment of Intestinal Adenomas in Familial Adenomatous Polyposis (FAP)
Colorectal cancer
Parallel Assignment Double Blind (Subject, Investigator)
NCT 00641147
Phase 2 Randomized controlled trial
Curcumin With Pre-operative Capecitabine and Radiation Therapy Followed by Surgery for Rectal Cancer
Rectal cancer Safey/Efficacy Study Single group Assignment Double Blind (Subject, Caregiver)
NCT 00745134
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Table 3 – Curcumin analogs and their benefits
Analog Study conclusion Benefits and aims
Reference
EF24 In ovarian cancer cells, VEGF was dose-dependently reduced with EF24 demonstrating 8-fold greater potency than curcumin (P < .05). Synergism with cisplatin.
Enhanced potency
Tan et al. (79)
Novel strategy curcumin analog EF24 with a p38 inhibitor for lung cancer
Enhanced potency
Thomas et al. (80)
In MDA-MB231 and PC3, EF-24 inhibits HIF-1 and genuinely disrupts the microtubule cytoskeleton unlike curcumin
Mechanism
Thomas et al. (81)
EF24 shows anticancer potency 10 times higher than curcumin, against lung, breast, ovarian, and cervical cancer cells by blocking the nuclear translocation of NF-kB
Enhanced potency
Kasinski et al. (82)
EF31 EF31 has greater potency in NF-kB activity inhibition compared to curcumin and another analog EF24 and its action mechanism is based on its anti-inflammatory and antisurvival activities.
Enhanced potency
Olivera et al. (83)
BDMCA Chemopreventive effect through prevention of circulatory oxidative stress is not by methoxy group but by the terminal phenolic moieties or the central 7-carbon chain
Mechanism, Structure, roles
Devasena et al. (84).
BDMCA is antioxidant and lipid peroxidation and antioxidant status could be used as markers for colon cancer chemoprevention using BDMCA
Mechanism, Biomarker
Devasena et al. (85).
CDF Combination of CDF and conventional 5-FU+Oxaliplatin could be an strategy for preventing the emergence of chemoresistant colon cancer cells
Overcoming resistance
Kanwar et al. (86)
CDF had better retention and bioavailability and the concentration of CDF in the pancreas tissue was 10-fold higher compared to curcumin
Improved bioavailability
Padhye et al. (87)
FLLL32 FLLL32 has biochemically superior properties and more specifically targets STAT3, a transcription factor
Enhanced specificity
Fossey et al. (88)
FLLL32 reduced expression of STAT3-target genes Enhanced specificity
Bill et al. (89).
GO-Y030 GO-Y030 has 30-fold higher potency in suppressing tumor cell growth compared with curcumin by inhibition of IKKβ
Enhanced potency
Sato et al. (90)
Improved chemopreventive effect with GO-Y030 compared with curcumin (191 days). Diminished polyp incidence in Apc(580D/+) mice fed GO-Y030.
Enhanced prevention
Shibata et al. (91)
DAP High levels of HO-3867 were detected in the liver, kidney, stomach, and blood 3 hours after DAP i.p. injection. Higher bioabsorption
Improved bioavailability
Dayton et al. (74)
[DLys(6)]-LHRH-Curcumin
The analog inhibited the proliferation of pancreatic cancer cell lines (p < 0.05) by inducing apoptosis. Water soluble and i.v. infusible. i.v. infusion could achieve significant tumor weight and volume (p < 0.01)
Targeted delivery
Aggarwarl et al. (92)
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Published OnlineFirst March 6, 2013.Cancer Prev Res Wungki Park, A.R.M. Ruhul Amin, Zhuo Georgia Chen, et al. New perspectives of curcumin in cancer prevention
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